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Ruff et al. Hepatoma Res 2023;9:37 https://dx.doi.org/10.20517/2394-5079.2023.51 Page 5 of 10

[33]
(ClarIDHy, NCT02989857) . They recruited 187 patients and randomized in a 2:1 fashion (ivosidenib vs.
placebo). The majority of patients had ICCA (91.4%). Of the 61 patients in the placebo arm, 43 crossed over
to the ivosidenib arm. Median OS was 10.3 months and 7.5 months with ivosidenib versus placebo,
respectively, but when adjusted for crossover, the median OS for the placebo cohort was 5.1 months
(P < 0.001). The most frequently reported grade 3 or higher adverse event in both cohorts was ascites. This
is the first randomized phase III trial that demonstrates the clinical benefit of targeting IDH1 mutations in
patients with previously treated CCA. The National Comprehensive Cancer Network (NCCN) guidelines
[36]
now recommend ivosidenib as a second-line therapy for patients with IDH1 mutated CCA .
LY3410738
LY3410738 is a selective, covalent inhibitor of IDH1 that binds to a different site of the mutated IDH1
enzyme than ivosidenib. LY3410738 modifies a single cysteine in an allosteric binding pocket and
inactivates the enzyme. This inhibits 2-HG production but does not change α-KG levels . Additionally, this
[37]
binding site is outside of the dimer interface, enabling activity in the setting of known second-site IDH1
mutations . In a pre-clinical study, LY3410738 demonstrated greater potency for inhibition of 2-HG
[38]
production in vitro compared to ivosidenib. Furthermore, the combination of LY3410738 and a Bcl-2
inhibitor was effective in an acute myeloid leukemia xenograft model that was derived from a patient with
ivosidenib resistance . LY3410738 is currently being evaluated in a phase I trial (NCT04521686) in patients
[37]
with IDH1 mutated solid tumors, including advanced CCA. This study includes patients who had previous
treatment with another IDH1 inhibitor. After determining the recommended phase II dose, LY3410738 will
be evaluated as a monotherapy and in combination with cisplatin and gemcitabine. The cohort with a
combination of LY3410738, gemcitabine, and cisplatin will be in patients with CCA who are
treatment-naïve .
[38]

Poly-ADP ribose polymerase inhibitors
Poly-ADP ribose polymerase (PARP) is a family of proteins that are involved in DNA repair. Wang et al.
demonstrated with pre-clinical in vitro and in vivo models of gliomas and cholangiocarcinoma that the IDH
[39]
mutation confers sensitivity to PARP inhibitors . However, this study also suggests that concurrent
radiation therapy is necessary to yield the maximum benefit of PARP inhibitors in these patients. Other
studies have proposed that the reason IDH-mutated CCA cell lines are sensitive to PARP inhibitors is
related to elevated levels of 2-HG [40,41] . Based on these studies, there are ongoing clinical trials evaluating
olaparib (PARP inhibitor) in patients with IDH-mutated CCA (NCT03w878095, NCT03212274,
NCT03561870, NCT03749187).

Platinum-based chemotherapy
Pre-clinical evidence also indicates that IDH1 and IDH2 mutations result in homologous recombination
deficiency. As a result, the cell is unable to effectively repair double-stranded DNA breaks . Some propose
[42]
that this could be exploited as a target for platinum-based chemotherapy and/or PARP inhibitors. In a
retrospective study, Niger et al. investigated whether there was a survival difference with platinum-based
therapy in patients with IDH-mutated versus wild-type ICCA . There was no difference in PFS, disease
[43]
control rate, or overall response rate when comparing patients with IDH-mutated ICCA to patients with
wild-type ICCA. In an analysis of the Cancer Genome Atlas CCA tumors, there was no difference in the
rate of homologous recombination deficiency between IDH-mutated and wild-type CCA tumors, although
CCA did have higher homologous recombination deficiency compared to other tumor types . This
[43]
suggests that the presence of IDH mutation does not necessarily correlate with elevated homologous
recombination deficiency.